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Kamalu, M.

Publications and source records attributed to Kamalu, M..

5 recordsLinked to original sources

Efficient transgene-free multiplexed genome editing via viral delivery of an engineered TnpB.

Virus-induced genome editing (VIGE) using compact RNA-guided endonucleases is a transformational new approach in plant biotechnology, enabling tissue-culture-independent and transgene-free genome editing (Hu et al. 2025; Liu et al. 2025; Weiss et al. 2025). We recently established a VIGE approach for heritable editing at single loci in Arabidopsis by delivering the compact genome editor ISYmu1 TnpB (Ymu1) and its guide RNA (gRNA) via Tobacco Rattle Virus (TRV) (Weiss et al. 2025). Here, we greatly improved this approach by devising a multiple gRNA expression system and by utilizing an engineered high-activity Ymu1 variant (Ymu1-WFR) (Zhou et al. 2026) to develop an efficient multiplexed genome editing platform.

plant biology↗

Stepwise DNA unwinding gates TnpB genome-editing activity

TnpB is a compact RNA-guided endonuclease and evolutionary ancestor of CRISPR-Cas12 that offers a promising platform for genome engineering. However, the genome-editing activity of TnpBs remains limited and its underlying determinants are poorly understood. Here, we used biochemical and single-molecule assays to examine the DNA-unwinding mechanism of Youngiibacter multivorans TnpB (Ymu1 TnpB). DNA unwinding proceeds through a discrete, long-lived partially unwound intermediate state before reaching a fully unwound open state. The open state forms inefficiently and collapses readily in the absence of negative supercoiling. An optimized variant, Ymu1-WFR, stabilizes formation of both the intermediate and open states, resulting in enhanced DNA cleavage in vitro and increased genome editing in plants. These findings identify the physical basis for the observed minimal activities of natural TnpBs, revealing how stabilizing specific unwinding states enables efficient DNA targeting.

biochemistry↗

Structure and evolution-guided design of minimal RNA-guided nucleases

The design of RNA-guided nucleases with properties not limited by evolution can expand programmable genome editing capabilities. However, generating diverse multi-domain proteins with robust enzymatic properties remains challenging. Here we use an artificial intelligence-driven strategy that couples structure-guided inverse protein folding with evolution-informed residue constraints to generate active, divergent variants of TnpB, a minimal CRISPR-Cas12-like nuclease. High-throughput functional screening of AI-generated variants yielded editors that retained or exceeded wild-type activity in bacterial, plant and human cells. Cryo-EM-based structure determination of the most divergent active variant revealed new stabilizing contacts in the RNA/DNA interfaces across conformational states, demonstrating the design potential of this approach. Together these results establish a strategy for creating non-natural RNA-guided nucleases and conformationally active nucleic acid binders, enlarging the designable protein space. One-sentence abstractAn evolution- and structure-conditioned model enables design of active RNA-guided nucleases with new nucleic acid contacts resolved by cryo-EM.

synthetic biology↗

Virus induced transgene- and tissue-culture free heritable genome editing in tomato

Genome editing has emerged as a powerful tool for genome manipulation and trait improvement in crops. However, most commonly used approaches rely on tissue culture and transgenic materials, which are time-consuming, labor-intensive, and often strongly genotype-dependent. Here, we developed a tobacco rattle virus (TRV)-based system to deliver the compact ISYmu1 TnpB endonuclease, coupled with in planta shoot regeneration, to achieve somatic and heritable genome editing across different tomato cultivars without tissue culture. By targeting SlPDS, we successfully generated virus-free homozygous mutant progeny in a single generation. Furthermore, we extended this system to the functional analysis of the previously uncharacterized SlDA1 locus, revealing its involvement in organ size regulation, and recovered transgene-free SlDA1 mutants displaying enlarged fruits. Given the wide host range of TRV, our system should be broadly applicable for rapid, non-transgenic and less genotype-dependent heritable genome editing, thereby advancing both functional genomics and crop improvement. SignificanceEfficient genome editing without the need for transgenesis or tissue culture remains a major challenge in crop breeding. Here, we establish a simple single-step system for transgene- and tissue culture-free genome editing in tomato based on Tobacco Rattle Virus-mediated delivery of the compact RNA-guided TnpB enzyme ISYmuI and its guide RNA. This strategy enabled somatic editing of de novo shoots and heritable transmission of targeted mutations to the next generation. Notably, editing an agronomically relevant gene produced tomato plants with larger fruits, highlighting the potential of this system for crop improvement.

plant biology↗

Viral delivery of an RNA-guided genome editor for transgene-free plant germline editing

AbstractGenome editing is transforming plant biology by enabling precise DNA modifications. However, delivery of editing systems into plants remains challenging, often requiring slow, genotype-specific methods such as tissue culture or transformation. Plant viruses, which naturally infect and spread to most tissues, present a promising delivery system for editing reagents. But most viruses have limited cargo capacities, restricting their ability to carry large CRISPR-Cas systems. Here, we engineered tobacco rattle virus (TRV) to carry the compact RNA-guided TnpB enzyme ISYmu1 and its guide RNA. This innovation allowed transgene-free editing of Arabidopsis thaliana in a single step, with edits inherited in the subsequent generation. By overcoming traditional reagent delivery barriers, this approach offers a novel platform for genome editing, which can greatly accelerate plant biotechnology and basic research.

plant biology↗